Chronic low-level inflammation is a hallmark of aging. However, the mechanistic links between chronic inflammation and cardiovascular diseases are not fully understood. As aging is one of the strongest independent risk factors for atherosclerosis, understanding this link is of critical importance to the clinical care of our ever increasing population of older people. In an experimental model of atherosclerosis (i.e., LDLr -/- mice), we found that aging leads to larger atherosclerotic lesions; increased production of macrophage chemo-attractants, CCL2 and osteopontin; peripheral monocytosis; and an increase in macrophage recruitment into the aorta. Our prior work demonstrates that without atherosclerosis, aged vascular smooth muscle cells (VSMC) contribute to the aortic inflammatory milieu by producing increased CCL2 and osteopontin. Importantly, we showed that the production of these inflammatory molecules depends on MyD88, an innate immune adaptor protein downstream of the Toll like receptors. We also found that aging impairs autophagosome formation within VSMC and is accompanied by increased mitochondrial mass and reactive oxygen species. Taken together, these findings suggest that damaged mitochondria accumulate in aging VSMC due to reduced autophagy, leading in turn to a buildup of mitochondrial components that activate MyD88 to enhance atherosclerosis. To test this hypothesis, we will use a new model system in which MyD88 is selectively and inducibly deleted within VSMC of aging atherosclerotic prone mice to examine the extent by which MyD88 expression within VSMC controls age-enhanced macrophage recruitment into the aorta and atherosclerosis. We will also use mice in which autophagy is disabled within VSMC, to determine if autophagy in VSMC controls basal inflammation, monocyte recruitment into the aorta, and the development of atherosclerosis. Our proposal will yield critical insights into how aging impacts inflammatory responses in VSMC to enhance atherosclerosis. Our findings may contribute to the development of novel therapies for atherosclerosis in the older population.

Public Health Relevance

Aging increases the risk of chronic inflammation and atherosclerosis. However, we lack a clear understanding of the interplay between aging and atherosclerosis. In this proposal, we will examine the mechanisms by which vascular smooth muscle cells promote macrophage recruitment to enhance atherosclerosis with aging.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fleg, Jerome L
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Goldstein, Daniel R; Jalife, José (2017) Synergistic Research Between the Center of Arrhythmia Research and the Michigan Biology of Cardiovascular Aging at the University of Michigan. Circ Res 121:1221-1223
Colvin, Monica M; Smith, Candice A; Tullius, Stefan G et al. (2017) Aging and the immune response to organ transplantation. J Clin Invest 127:2523-2529
Jane-Wit, Dan; Fang, Caodi; Goldstein, Daniel R (2016) Innate immune mechanisms in transplant allograft vasculopathy. Curr Opin Organ Transplant 21:253-7